Acyl pyrones

ABSTRACT

PROCESS FOR THE PRODUCTION OF ALIPHATIC 2,4-DIENOIC ACIDS AND ESTERS THEREOF WHICH COMPRISES CONDENSING AN ALDEHYDE SUCH AS DEHYDROCITRONELLAL WITH AN ESTER OF BETA-METHYLGLUTACONIC ACID, ACIDIFICATION OF THE 1,4-DIACID SALT TO THE FREE 1,4-DIACID AND DECARBOXYLATION TO THE C-1 ACID AND NOVEL INTERMEDIATES.

United States Patent Olfice 3,773,793 Patented Nov. 20, 1973 3,773,793ACYL PYRONES Clive A. Henrick, Palo Alto, Calif., assignor to ZoeconCorporation, Palo Alto, Calif. No Drawing. Filed Aug. 7, 1972, Ser. No.278,328 Int. Cl. C07d 7/16 U.S. Cl. 260-3435 Claims ABSTRACT OF THEDISCLOSURE This invention relates to the syntheses of aliphatic 2,4-dienoic acids and esters thereof, novel intermediates therefor, and thecontrol of insects.

The syntheses of the present invention are directed to the production ofaliphatic 2,4-dienoic acids and esters of Formula A.

each of R R and R is methyl or ethyl;

R is hydrogen or methyl;

R is hydrogen, lower alkyl, cycloalkyl, lower alkenyl or lower alkynyl;and

Z is hydrogen, hydroxy or lower alkoxy.

The compounds of Formula A are useful for the control of insects such asDiptera, Homoptera, Lepidoptera, Coleoptera and Hemiptera. See Chemical& Engineering News, 49, 33, Nov. 29, 1971 and Belgian Pats. 778,241 and778,242 (1972). The more active isomer of the compounds of Formula A isthe trans (2), trans (4) isomer. A principal advantage of the presentinvention is the economical and advantageous production of compounds ofFormula A in which formation of the trans, trans isomer is favored overthe cis (2), trans (4) isomer.

Hereinafter, each of R, R R R R and Z is as defined above, unlessotherwise specified.

Briefly stated, the syntheses of the present invention comprises thecondensation of an aldehyde such as dihydrocitronellal with an ester ofbeta-methylglutaconic acid resulting in a 1,4-diacid, decarboxylation ofthe 1,4-diacid to the C-1 acid which is essentially all cis (2), trans(4) acid and conversion thereof into trans (2), trans (4) acid or ester.

The syntheses of the present invention is outlined as follows (R' islower alkyl and M is sodium or potassium):

In the practice of the above outlined syntheses, an aldehyde of FormulaI is condensed with a lower alkyl ester of beta-methylglutaconic acid ofFormula II to yield the diacid salt (III). The condensation is conductedH: =CH-CO2R' (II) using about a one to one mole ratio of the aldehyde(I) and ester (II) and about two to four equivalents of a base such assodium hydroxide or potassium hydroxide in a lower monohydric alcoholsolvent such as methanol or ethanol. The reaction temperature can rangefrom room temperature to the reflux temperature of the reaction mixture.The reaction time which will vary with the temperature is from about onehour to forty-eight hours. A mixed ester of Formula II can be used aswell-i.e., R represents difierent alkyl radicals. In place of thediester II, these can be used lower alkyl isodehydroacetate such asmethyl or ethyl isodehydroacetate in the condensation reaction withaldehyde I to form' the di-salt III. On completion of the condensation,the reaction product can be washed with a non-polar organic solvent suchas a hydrocarbon or ether solvent, e.g., pentane, hexane or ether. Thediacid salt (III) is then dissolved in water or aqueous organic solventmedium and the solution adjusted to an acidic pH such as about pH 2 to 4using an inorganic or organic acid to yield the free diacid (IV). Thediacid (IV) goes into the organic phase upon acidification of theaqueous organic solvent medium. Alternatively, after acidification of awater solution of III, extraction with an organic solvent removes thefree acid (IV). The diacid (IV) is essentially exclusively cis at C2,3while configuration at C-4,5 is uncertain. Suitable organic solventsinclude the ethers and hydrocarbons. Either an inorganic or organic acidor a reagent capable of releasing acid can be used for acidification.Suitable agents for acidification include, for example, sulfuric acid,hydrochloric acid, phosphoric acid and acetic acid.

The diacid (IV) is then decarboxylated to the C-1 monoacid (V) which isessentially exclusive cis (2), trans (4). The decarboxylation isconducted with heating in a tertiary organic amine in the presence orabsence of a copper salt or metallic copper. Suitable amines include2,4-dimethylpyridine, 2,4,6-trimethylpyridine, pyridine, and the like.Suitable copper salts include copper diacetate, copper sulfate, copperoxide, copper chromite cuprous acetate, cuprous oxide, and the like.Organic solvent inert to the reaction can be added such as a hydrocarbonsolvent along with the amine and copper salt. The reaction appears tobegin at about C. at which time carbon dioxide is given off and iscompleted at about C. to C. to form the cis (2), trans (4) monoacid (V).One or both of the intermediate lactones VI and VII may be present inthe reaction product of the decarboxylation of the diacid IV dependingupon reaction temperature, reaction time, presence or absence of copper,and the amount of amine as will be apparent from the exampleshereinafter. Any unconverted lactone VI and VII can be recycled ortreated separately by heating with organic amine or other base to theacid (V). The presence of a tertiary amine and/or copper is notessential in the decarboxylation step as is demonstrated hereinafter.

The diacid IV on standing will form an acid lactone of the Formula VIIIand, without any intentions of being bound by theory, is probably formedduring the decarboxylation of the diacid IV to the mono-acid V. The acidlactone VIII is readily converted into the mono-acid V as demonstratedhereinafter.

The cis-2, trans-4 mono-acid V is then isomerized to a mixture oftrans-2, trans-4, and cis-2, trans-4 by treatment with isomerizationcatalysts such as diphenylsulfide, thioacetic acid, phenyl mercaptan,and the like in the presence or absence of a free radical initiator suchas 2,2'-azobis (isobutyronitrile). An equilibrium mixture is achieved ofthe order of 60% trans-2, trans-4 and 40% cis-2, trans-4. The isomericmixture is then esterified in a conventional manner, see for example,Belgian Pats. 718,241 and 718,242, to prepare the useful esters ofFormula A. One suitable method is to treat the acid with thionylchloride to form the acid chloride which is then reacted with an alcoholof Formula ROH such as isopropanol, ethanol, n-propanol, propargylalcohol or prop- 2-en-l-al according to the ester moiety desired.

Alternatively, the cis-2, trans-4 acid V can be esterified first andthen isomerized using, e.g., elemental sulfur, sodium sulfide, lithium,potassium or sodium salt of methylmercaptan or sodium hydrogen sulfideto prepare a mixture of the trans-2, trans-4 and cis-2, trans-4 isomersof Formula A.

The term lower alkyl, as used herein, refers to a straight or branchedchain saturated aliphatic hydrocarbon group having a chain length of oneto six carbon atoms, e.g., methyl, ethyl, propyl, i-propyl, n-butyl,s-butyl, t-butyl, pentyl and hexyl.

The term lower alkoxy, as used herein, refers to lower alkoxy group ofone to six carbon atoms such as methoxy, ethoxy, isopropoxy, t-butoxyand n-propoxy.

The term cycloalkyl, as used herein, refers to a cyclic alkyl groupcontaining three to eight carbon atoms, e.g. cyclopropyl, cyclopentyland cyclohexyl.

The term lower alkenyl, as used herein, refers to an ethylenicallyunsaturated hydrocarbon group, branched or straight chain, having a,chain length of two to six EXAMPLE 1 To a mixture of 25 g. of dimethylp-methylglutaconate, 25 g. of 7-hydroxy-3,7-dimethyloctan-l-al, andabout 20 ml. of methanol is added 18 g. of sodium hydroxide partiallydissolved in 35 ml. of methanol. The reaction is stirred at gentlereflux for 1.5 hours, under nitrogen. A thick slurry is formed which iscooled to about 9, filtered and washed with ether to yield the disodiumsalt (111; each of R R and R is methyl, R is hydrogen, 2 is hydroxy andM is sodium).

About 3 g. of the disodium salt in water is acidified by addition ofsulfuric acid (3 N) with stirring. The mixture is extracted with ether(3X), Washed with water and saturated sodium chloride, and put undervacuum to yield the free diacid (IV; each of R R and R is methyl, R ishydrogen, Z is hydroxy), pale yellow crystals.

To 1.2 g. of the diacid in 2.8 g. of lutidine (2,4-dimethylpyridine),under nitrogen, is added 23.6 mg. of copper diacetate monohydrate. Thereaction mixture is slowly heated up to about 120-145 and then heated atabout 130 for twenty minutes. The reaction is worked up by cooling andadding to ml. of ether and 75 ml. of water. Sulfuric acid (2 N) is addedto adjust to about pH one and then extracted with ether. Ether phase iswashed with saturated copper sulfate solution, water and saturated NaCl,dried over calcium sulfate, filtered and filtrate evaporated to yield1l-hydroxy-3,7,1l-trimethyldodeca-2,4-dienoic acid (V; each of R, R andR is methyl, R is hydrogen, Z is hydroxy), essentially all cis (2),trans (4), colorless, rather viscous oil.

To 100 mg. of the above mono-acid in 2.5 ml. of ether, under nitrogen,at room temperature is added about 0.79 millimole ofl-ethyl-3-p-tolyltriazene in 2.5 ml. of ether. The reaction is heated toreflux for 4 hours and then cooled. The reaction is worked up by washingwith ice water, aqueous dilute HCl, aqueous sodium bicarbonate andsaturated NaCl, dried over calcium sulfate, filtered and filtrateevaporated to remove solvent to yield ethyl11-hydroxy-3,7,1l-trimethyldodeca-2,4-dienoate as a mixture of 96.3% cis(2), trans (4) and 3.7% trans (2), trans (4) isomers.

EXAMPLE 2 To a mixture of 1.0 g. of diethyl beta-methylglutaconate, 0,78g. of 7-methoxy-3,7-dimethyloctan-l-al and 0.5 ml. of methanol at 24under nitrogen, is added a mixture of 1.12 g. of potassium hydroxide and6 ml. of methanol. The mixture is stirred at room temperature for 20hours, cooled to 0 and filtered to yield the dipotassium salt (III; eachof R R and R is methyl, R is hydrogen, Z is methoxy, M is potassium),cream-colored dry solid. The dipotassium salt is dissolved in 4 ml. ofwater which is acidified (pH 2) with 3 N sulfuric acid and extractedwith ether. The ether phase is Washed with Water and saturated NaCl,dried over calcium sulfate and solvent evaporated to yield the diacid(IV; each of R R and R is methyl, R is hydrogen, Z is methoxy), veryviscous, light yellow liquid.

A mixture of 0.47 g. of the above diacid, 1.55 g. of 2,4-lutidine and 8mg. of copper diacetate powderis heated to for 30 minutes. The mixtureis cooled and 50 ml. of ether and 25 ml. of water added. The pH of themixture is brought to zero with 3 N sulfuric acid. The aqueous phase isseparated and extracted twice with 25 ml. portions of ether. Thecombined ether layers are washed twice with 10 ml. portions of saturatedaqueous copper sulfate, twice with 10 ml. portions of water, and oncewith 10 ml. of saturated aqueous NaCl, dried over calcium sulfate andsolvent evaporated to yield 11-11116-(boxy-3,7,11-trimethyldodeca-2,4-dienoic acid, pale yellow liquid,consisting almost entirely of the cis (2), trans (4) isomer.

EXAMPLE 3 A mixture of 0.34 g. of 1l-methoxy-3,7,ll-trimethyl'dodeca-Z-(cis), 4 (trans)-dienoic acid, 0.19 ml. of thionyl chloride,and 3 ml. of ether is heated at 35", under nitrogen, in a water bath,for one hour. Then, the mixture is concentrated by evaporation to removevolatile materials. To the concentrate is added 2 ml. of ether and 0.16ml. of isopropanol at The mixture is allowed to warm to room temperatureand then 50 ml. of ether and 50 ml. of water are added. The ether layeris separated, washed twice with 10 ml. portions of water and once with10 n1]. of saturated aqueous NaCl, dried over calcium sulfate, andevaporated to yield isopropyl 1l-methoxy-3,7,11-trimethyldodeca-Z (cis),4 (trans)-dienoate, pale yellow liquid.

EXAMPLE 4 Following the procedure of Example 2, 1.51 g. of the diacid(IV; each of R R and R is methyl, R is hydrogen, Z is methoxy) isdecarboxylated using 25.2 mg. of copper diacetate and 4.72 g. of2,4-lutidine and heating at 80-120 for 30 minutes to yield 1.08 g. (84%yield) of 11-methoxy-3,7,11-trimethyldodeca-2 (cis), 4 (trans)-dienoicacid, pale yellow liquid.

EXAMPLE 5 To a mixture of 0.5 g. of diacid (IV: Z is hydrogen, each of RR and R is methyl, R is hydrogen) and 3 ml. of toluene is added mg. ofcuprous oxide powder. The mixture is heated on an oil bath slowly up toabout 96 for 2.8 hours. Then 21 mg. of collidine is added and heatingcontinued for 0.7 hour. Heat is removed and after cooling, the reactionis filtered. The filtrate is added to water and acidified to about pHone using 4 N sulfuric acid. The phases are separated and the aqueousphase extracted with ether. The combined organic phases are washed withwater and brine, dried over Drierite, filtered and the filtrateconcentrated to yield mostly the lactone (VII; each of R R and R ismethyl, R is hydrogen, Z is hydrogen) and a small amount of3,7,11-trimethyldodeca-2,4dien vic acid (essentially all cis 2, trans 4)which are separated by thin layer chromatography using ether/hexane(7/3).

EXAMPLE 6 A mixture of 0.7 g. of diacid (IV; each of R R and R ismethyl, R is hydrogen, Z is hydrogen), 25 mg. of cupric acetatemonohydrate and 3 ml. of 2,4-lutidine, under nitrogen, is heated to 80and then heat removed when generation of carbon dioxide ceases (about 30minutes). Mixture is allowed to cool, then poured into water andacidified to about pH one using 4 N sulfuric acid. The mixture isextracted with ether (3 x). The combined ether extracts are washed withsaturated copper sulfate solution, water and brine, dried over calciumsulfate and solvent removed by evaporation to yield a mixture (orangeviscous liquid) containing the cis 2, trans 4 acid V (Z is hydrogen,each of R R and R is methyl, R is hydrogen), the lactone VII (Z ishydrogen, each of R R and R is methyl, R is hydrogen) and the lactone VI(Z is hydrogen, each of R R and R is methyl, R is hydrogen) which areseparated by preparative thin layer chromatography eluting withetherzhexane (4:6)

containing 1% formic acid.

EXAMPLE 7 of 2.4 g. of sodium hydroxide and 20 ml. of dry methanolslowly, with stirring. After addition is complete, the reaction mixtureis heated at reflux for about 2.5 hours. Heat is removed and mixtureallowed to cool and then filtered to collect the precipitated disodiumsalt (III; M is sodium, Z is hydrogen, each of R, R and R is methyl, Ris hydrogen) as a fine powder which is washed with ether and thendissolved in water and the solution adjusted to pH one with 4 N sulfuricacid. The Water is separated off and the residue taken up in ether. Theseparated water is washed with ether. The combined ether phases arewashed with water and brine, dried over calcium sulfate and solidevaporated to yield the diacid (IV; Z is hydrogen, each of R R and R ismethyl, R is hydrogen) as a very light yellow, thick viscous liquidwhich solidifies on standing at room temperature, about 75% yield.

EXAMPLE 8 To a mixture of 250 g. of 7-methoxy-3,7-dimethyloctan-l-al,325 g. of dimethylglutaconate, and 150 ml. of dry methanol is slowlyadded, under a slow nitrogen flow and with stirring, a solution of 267g. of sodium hydroxide pellets in 1000 ml. of dry methanol. Afteraddition is complete, the reaction mixture is heated to reflux for aboutone hour and then heat removed and flask cooled in ice water bath. Themixture is filtered and the yellow cake (disodium salt, III; M issodium, Z is methoxy, R is hydrogen, each of R R and R is methyl) iswashed with ether and then dissolved in about 1500 ml. of water. Theaqueous solution is adjusted to about pH one and then extracted withether (3x). The combined ether extracts are washed with 'water andbrine, dried over calcium sulfate, filtered and filtrate evaporated toremove solvent to yield the free diacid IV (Z is methoxy, R is hydrogen,each of R R and R is methyl), yield about 86.5%.

EXAMPLE 9 To a solution of 0.5 g. of diacid (IV; X is hydrogen, R ishydrogen, each of R R and R is methyl) and 3 ml. of collidine(2,4,6-trimethylpyridine), under nitrogen, is added 11 mg. of cupricacetate. The reaction mixture is heated up to 125 over about 0.5 hourand then maintained at 125 for about 0.5 hour. The mixture is allowed tocool, ether added and then poured into water. This mixture is acidifiedusing 4 N sulfuric acid to pH 3.5 and then separated. Aqueous phase isextracted with ether. The combined ether phases are washed withsaturated copper sulfate solution, water and brine, dried over calciumsulfate, filtered and filtrate evaporated to remove solvent to yield3,7,1l-trimethyldodeca-2,4-dienoic acid, essentially all cis 2, trans 4.

EXAMPLE 10 A mixture of 1.0 g. of methyl 3,7,11-trimethyldodeca-2 (cis),4 (trans)-dienoate and 30 mole percent of sodium EXAMPLE 1 l A mixtureof 250 mg. of ll-methoxy-3,7,ll-trimethyldodeca-2 (cis), trans(4)-dienoic acid and 39 mg. of phenyldisul-fide is heated at for 8hours. After cooling, the mixture which is about 60% trans (2), trans(4) isomer and about 40% cis (2), trans (4) isomer of the startingmaterial can be distilled or crystallized at low temperature (about 0)for purification.

7 EXAMPLE 12 (A) To a solution of 302 g. (0.965 mole) of diacid (IV; Zis methoxy, each of R R and R is methyl, R is hydrogen) and 2000 ml. ofdry toluene, under nitrogen, is added 10.3 g. (0.0965 mole) of2,4-lutidine and then 6.71 g. of copper diacetate. The reaction isheated up to about 105-107" which is maintained for about two hours andthen allowed to cool. The reaction mixture is poured into water andacidified using 4 N sulfuric acid. The aqueous phase is extracted withtoluene. The combined toluene solutions are then washed with saturatedcopper sulfate solution, water and brine, dried over calcium sulfate andafter one hour the solution is filtered and concentrated under vacuum togive a 93% product yield of a mixture of the deconjugated lactone (VII;Z is methoxy, R is hydrogen, and each of R R and R is methyl) and cis(2), trans (4) acid (V; Z is methoxy, R is hydrogen, each of R R and Ris methyl) which can be separated by chromatography, if desired.

(B) To a solution of 0.28 g. of sodium and ml. of absolute ethanol,under nitrogen, with stirring, is added 2.64 g. of the product from part(A) above in 10 ml. of absolute ethanol. The reaction is stirred at roomtemperature for about 1.5 hours and then heated to reflux for about 4hours. Heat is removed and mixture stirred overnight at roomtemperature. Ethanol is evaporated ofi. Water is added to the residueand extracted with ether which is dried. The aqueous phase is acidifiedwith 4 N sulfuric acid and extracted (2X) with ether. The combined ethersolutions are washed with water and brine and dried. The combined etherphases are filtered and concentrated under vacuum to yield11-methoxy-3,7,11- trimethyldodeca-Z (cis), 4 (trans)-dienoic acid, 84%yield.

EXAMPLE 13 A mixture of 1.065 g. of conjugated lactone (VI; each of Zand R is hydrogen, each of R R and R is methyl) and 5 ml. of ethanol isadded slowly to a solution of sodium ethoxide (0.115 g. of sodium and7.5 ml. of ethanol) at 3-5, under nitrogen. After addition is complete,the mixture is warmed to room temperature and stirred for about 17hours. The reaction is worked up by evaporating off the ethanol andadding the residue to ether and water which is acidified with 10% HCl.The aqueous layer is extracted with ether (3X) and the organic layersare combined and washed with water and saturated NaCl solution. Dryingover calcium sulfate, filtering and evaporating the solvent gives3,7,11-trimethyldodeca-2 (cis), 4 (trans)-dienoic acid in about 86%yield.

EXAMPLE 14 To a mixture of 4.9 g. of ethyl isodehydroacetate, 3.9 g. of3,7-dimethyloctan-1-al and about 10 ml. of methanol, is slowly added asolution of 5.6 g. of KOH and 25 ml. of methanol, with cooling. Thereaction mixture is stirred overnight. After cooling to about --5 to 0,the mixture is filtered and the filter cake (III; M is potassium, eachof R and Z is hydrogen, each of R R and R is methyl) is dissolved inwater, acidified to pH one with 4 N sulfuric acid and extracted withether (3 X). The combined ether extracts are washed with water, driedover calcium sulfate and evaporated under reduced pressure to yield thediacid (IV; each of Z and R is hydrogen, each of R R and R is methyl).

The above process is repeated using an equivalent amount of7-methoxy-3,7-dimethy1oetan-l-al in place of 3,7-dimethyloctan-1-al toyield as the final product the diacid (IV; Z is methoxy, R is hydrogen,each of R R and R is methyl).

EXAMPLE 15 To a slurry of 3.56 g. (0.01 mole) of disodium salt (III; Zis methoxy, R is hydrogen, each of R R and R is methyl, M is sodium) and50 ml. of ether is added 0.54 ml. of concentrated sulfuric acid,dropwise. After stirring for 0.75 hour at room temperature, the mixtureis filtered to remove the sodium sulfate. After most of the ether isremoved at water aspirator pressure, 2.4 ml. (0.03 mole) of pyridine -isadded. The remainder of the ether is removed at water aspiratorpressure, and the reaction mixture is heated at under nitrogen, for tWohours (after one hour carbon dioxide evolution ceases). The pyridine isstripped off the reaction mixture at 0.1 mm. Hg at room temperatureover'a two hour period. The residual oil is taken up in ether and washedwith 1.4 N sodium hydroxide. The organic phase is separated, dried overmagnesium sulfate, filtered and pumped to constant weight. The residueis a mixture ofconjugated lactone (VI; Z is methoxy, R is hydrogen, eachof R R and R is methyl) and deconjugated lactone (VII; Z is methoxy, Ris hydrogen, each of R R and R is methyl) which can be separated by thinlayer chromatography, if desired. The combined aqueous sodium hydroxidewashings are acidified to pH one using 3.6 N sulfuric acid and extracted(3 X) with ether. The ether extracts are combined and dried overmagnesium sulfate. Removal of drying agent and ether yields11-methoxy-3,7,11-trimethyldodeca-Z (cis), trans (4)-dienoic acid.

EXAMPLE 16 A mixture of 0.01 mole of diacid (IV; Z is methoxy, R ishydrogen, each of R R and R is methyl) and 0.03 mole of 2,4-lutidine isheated to under nitrogen, for two hours. The reaction is worked up asdescribed in Example 15 to yield the same deconjugated lactone VII,conjugated lactone VI, and cis (2), trans (4) acid V as in Example 15.

EXAMPLE 17 (A) A mixture of 5 g. of diacid (IV; Z is methoxy, R ishydrogen, each of R R and R is methyl) and 30 ml. of dry other isallowed to stand at room temperature for one month in a stopperedvessel. The ether is evaporated off to yield predominantly the lactoneacid of the following formula EXAMPLE 18 (A) The process of Example 17(part A) is repeated using the diacid (IV; each of Z and R is hydrogen,each of R R and R is methyl) to yield the following acid lactone andsome of the diacid starting material.

(B) The process of part B of Example 17 is repeated using the product ofpart A of this example as the starting material to yield the conjugatedlactone VI, deconjugated lactone VII and cis (2), trans (4) acid Vwherein each of Z and R is hydrogen and each of R, R and R is methyl.

(C) The acid lactone of part A of this example can be prepared by analternative method consisting of heating the diacid IV (Z is hydrogen)in acetone in the presence of 50% aqueous sulfuric acid according to theprocedure of Wiley and Ellert, J. Am. Chem. Soc. 79, 2266 (1957).

EXAMPLE 19 To 3.56 g. (0.01 mole) of disodium salt (III; Z is methoxy, Mis sodium, R is hydrogen, each of R R and R is methyl) in 20 ml. ofwater is added 2.77 ml. of 3.6 N sulfuric acid. The pH of the resultingsolution is 6.5. The solution is refluxed for seven hours, after whichtime the pH is 8.5. After standing overnight at room temperature, themixture is made more basic by addition of 2 N sodium hydroxide and thenextracted with ether. The ether extracts are combined, dried overmagnesium sulfate and filtered. Removal of solvent yields a colorlessoil which is a mixture of about 55:45 of-meth0xy-2,6,10-trimethylundeca-1,3-diene and the conjugated lactone(VI; Z is methoxy, R is hydrogen, each of R R and R is methyl) which canbe separated by thin layer chromatography. The aqueous phase isacidified with 3.6 N sulfuric acid and extracted (3X) with ether. Theextracts are combined, dried over magnesium sulfate, filtered andsolvent stripped off. The residue is about a 2:1 mixture of11-methoxy-3,7,1l-trimethyldodeca-Z (cis), 4 (trans) dienoic acid and4-carboxy-11-meth0xy-3,7,ll-trirnethyldodeca-2 (cis), 4-dienoic acidwhich can be separated by thin layer chromatography.

EXAMPLE 20 To 2.005 g. of 11-methoxy-3,7,11-trimethyldodeca-2- (cis), 4(trans)-dienoic acid in a vial with a serum cap is added 44.4 mg. ofthiophenol and 13 mg. of 2,2-azobis (isobutyronitrile). The reactionmixture is heated to 80 for two hours. After cooling, the reactionmixture is dissolved in 3 ml. of dry ether and then distilled thionylchloride (1.07 ml.) in 17 ml. of dry ether is added slowly at roomtemperature under nitrogen. The mixture is heated for three hours at 35.Then, the ether is evaporated and fresh dry ether (20 ml.) added to theresidue (acid chloride mixture) which is cooled to about 1, undernitrogen. A mixture of 1.7 ml. of dry isopropanol and 5 ml. of ether isadded and the resulting reaction mixture stirred at about 2 for 0.5 hourand then warmed to room temperature and stirred for about 16 hours.Solvent and excess isopropanol is evaporated oif yielding isopropyl- 11methoxy-3,7,11 trimethyldodeca 2,4 dienoate having an isomer ratio of67.6% trans (2), trans (4) and 32.4% cis (2), trans (4).

EXAMPLE 21 wherein, each of R R and R is methyl or ethyl; R is hydrogenor methyl; and Z is hydrogen, hydroxy or lower alkoxy.

2. A compound according to claim 1 wherein each of R R and R is methyl.

3. A compound according to claim 2 wherein Z is hydrogen and R ishydrogen.

4. A compound according to claim 2 wherein Z is methoxy and R ishydrogen.

5. A compound according to claim 2 wherein Z is hydroxy and R ishydrogen.

References Cited UNITED STATES PATENTS 3,248,187 4/ 1966 Bell 260-343.5

DONALD G. DAUS, Primary Examiner A. M. T. TIGHE, Assistant Examiner U.S.Cl. X.R.

260-4055, 485 R, 535 P, 537 N 601 R, 602

